The neurotrophic factor MANF regulates autophagy and lysosome function to promote proteostasis in Caenorhabditis elegans

• 成果类型: Article
• 署名作者: Taylor, Shane K. B.; Hartman, Jessica H.; Gupta, Bhagwati P.
• 署名单位: McMaster University; Medical University of South Carolina; Medical University of South Carolina
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15340
• DOI: 10.1073/pnas.2403906121
• 发表日期: 2024-10-22
• 关键词: unfolded protein response; lipid-metabolism; stress; tfeb; endocytosis; expansion

摘要

The conserved mesencephalic astrocyte- derived neurotrophic factor (MANF) is known for protecting dopaminergic neurons and functioning in various other tissues. Previously, increased endoplasmic reticulum (ER) stress, dopaminergic neurodegeneration, and abnormal protein aggregation. These findings suggest an essential role for MANF in cellular processes. However, the mechanisms by which intracellular and extracellular MANF regulate broader cellular functions remain unclear. We report a unique mechanism of action for MANF- 1 that involves the transcription factor HLH- 30/TFEB- mediated signaling to regulate autophagy and lysosomal function. Multiple transgenic strains overexpressing MANF- 1 showed extended lifespan of animals, reduced protein aggregation, and improved neuronal survival. Using fluorescently tagged MANF- 1, we observed tissue- specific localization of the protein, which was dependent on the ER retention signal. Further subcellular analysis showed that MANF- 1 localizes within cells to the lysosomes and utilizes the endosomal pathway. Consistent with the lysosomal localization, our transcriptomic study of MANF- 1 and analyses of autophagy regulators demonstrated that MANF- 1 promotes proteostasis by regulating autophagic flux and lysosomal activity. Collectively, our findings establish MANF as a critical regulator of stress response, proteostasis, and aging.